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BACKGROUND: Thalamic abnormalities in schizophrenia are recognized, alongside cognitive deficits. However, the current findings about these abnormalities during the prodromal period remain relatively few and inconsistent. This study applied multimodal methods to explore the alterations in thalamic function and structure and their relationship with cognitive function in first-episode schizophrenia (FES) patients and ultra-high-risk (UHR) individuals, aiming to affirm the thalamus's role in schizophrenia development and cognitive deficits. METHODS: 75 FES patients, 60 UHR individuals, and 60 healthy controls (HC) were recruited. Among the three groups, gray matter volume (GMV) and functional connectivity (FC) were evaluated to reflect the structural and functional abnormalities in the thalamus. Pearson correlation was used to calculate the association between these abnormalities and cognitive impairments. RESULTS: No significant difference in GMV of the thalamus was found among the abovementioned three groups. Compared with HC individuals, FES patients had decreased thalamocortical FC mostly in the thalamocortical triple network, including the default mode network (DMN), salience network (SN), and executive control network (ECN). UHR individuals had similar but milder dysconnectivity as the FES group. Furthermore, FC between the left thalamus and right putamen was significantly correlated with execution speed and attention in the FES group. CONCLUSIONS: Our findings revealed decreased thalamocortical FC associated with cognitive deficits in FES and UHR subjects. This improves our understanding of the functional alterations in thalamus in prodromal stage of schizophrenia and the related factors of the cognitive impairment of the disease. TRIAL REGISTRATION: ClinicalTrials.govNCT03965598; https://clinicaltrials.gov/ct2/show/NCT03965598.
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Brain structural abnormality has been observed in the prodromal and early stages of schizophrenia, but the mechanism behind it is not clear. In this study, to explore the association between cortical abnormalities, metabolite levels, inflammation levels and clinical symptoms of schizophrenia, 51 drug-naive first-episode schizophrenia (FES) patients, 51 ultra-high risk for psychosis (UHR), and 51 healthy controls (HC) were recruited. We estimated gray matter volume (GMV), cortical thickness (CT), concentrations of different metabolites, and inflammatory marks among four groups (UHR converted to psychosis [UHR-C], UHR unconverted to psychosis [UHR-NC], FES, HC). UHR-C group had more CT in the right lateral occipital cortex and the right medial orbito-frontal cortex (rMOF), while a significant reduction in CT of the right fusiform cortex was observed in FES group. UHR-C group had significantly higher concentration of IL-6, while IL-17 could significantly predict CT of the right fusiform and IL-4 and IL-17 were significant predictors of CT in the rMOF. To conclude, it is reasonable to speculate that the increased CT in UHR-C group is related to the inflammatory response, and may participate in some compensatory mechanism, but might become exhaustive with the progress of the disease due to potential neurotoxic effects.
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Corteza Cerebral , Imagen por Resonancia Magnética , Esquizofrenia , Humanos , Esquizofrenia/patología , Esquizofrenia/diagnóstico por imagen , Masculino , Femenino , Adulto Joven , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Adulto , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , AdolescenteRESUMEN
BACKGROUND: The effect of childhood trauma on Internet gaming disorder remains unclear. In this study, we examined this association in Chinese students and explored the possible associated roles of psychological resilience and depression. METHODS: In total, 8,579 students from Hunan Province, China, provided information regarding their sociodemographic factors, history of childhood trauma, any symptoms of depression, psychological resilience, and characteristics of Internet gaming disorder for this cross-sectional study. The impact of childhood trauma on Internet gaming disorder, as well as the extent to which it was mediated by depression and moderated by psychological resilience was evaluated. RESULTS: The influence of childhood trauma on Internet gaming disorder was partially mediated by depression (B = 0.07, 95% CI [0.04, 0.05], p < 0.001), with psychological resilience acting as a mitigating factor (B = -0.002, 95% CI [13.74, 21.72], p < 0.001). Psychological resilience also moderated the association between childhood trauma and depression (B = - 0.003, 95% CI [22.17, 28.10], p < 0.001). Our moderated mediation model elucidated psychosocial mechanisms, revealing the underlying link between childhood trauma and Internet gaming disorder. It also demonstrated the partial mediating role of depression and modulating role of psychological resilience among Chinese students. CONCLUSIONS: Education and interventions, along with effective social support, should be provided to enhance students' psychological resilience and prevent childhood trauma and depression.
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Experiencias Adversas de la Infancia , Depresión , Trastorno de Adicción a Internet , Análisis de Mediación , Resiliencia Psicológica , Humanos , Masculino , Trastorno de Adicción a Internet/psicología , Femenino , China , Estudios Transversales , Depresión/psicología , Experiencias Adversas de la Infancia/psicología , Adulto Joven , Adolescente , Adulto , Juegos de Video/psicología , Estudiantes/psicologíaRESUMEN
OBJECTIVE: Patients with psychotic diseases have been reported to exhibit abnormalities in their olfactory discrimination. These alterations have also been identified in people at high genetic or clinical risk for psychosis, suggesting olfactory discrimination dysfunction may be a potential risk factor for developing psychosis. Thus, the purpose of our study is to explore the difference in olfactory discrimination ability in the prosal stage and early stage of psychosis and to explore the potential risk factor of developed psychosis. METHODS: We compared olfactory identification and cognitive function in 89 ultra-high-risk (UHR) individuals, 103 individuals with Drug-naïve first-episode schizophrenia (FES), 81 genetic high-risk (GHR) individuals, and 97 healthy controls (HC). Additionally, we compared olfactory identification and cognitive function between two groups; UHR individuals who later transitioned to psychosis (UHR-T; n = 33) and those who did not transition (UHR-NT; n = 42)). Furthermore, we analyzed the correlations between olfactory discrimination ability and cognitive function and symptoms and compared the olfactory function between men and women. RESULTS: Patients with first-episode schizophrenia (FES) and those at ultra-high risk (UHR) for psychosis exhibited more significant deficits in olfactory identification than healthy controls (HC), while no differences in olfactory identification dysfunction were observed between the genetic high risk (GHR) and HC groups. Notably, individuals in the UHR group who later developed psyhchosis displayed a steeper marked decline in their baseline olfactory identification ability than that of those in the UHR group who did not develop psychosis. Cognitive dysfunction is widely observed in both the FES and UHR groups, with a distinct correlation identified between olfactory discrimination function and cognitive performance. Finally, overall, women exhibit significantly superior olfactory function than men. CONCLUSION: In conclusion, these findings suggest that impairment of olfactory identification exists in the early stage of psychosis. Olfactory identification dysfunction may therefore be a potential marker of predicting the transition to schizophrenia.
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Trastornos del Olfato , Trastornos Psicóticos , Humanos , Masculino , Femenino , Trastornos Psicóticos/complicaciones , Adulto Joven , Adulto , Esquizofrenia/fisiopatología , Esquizofrenia/complicaciones , Discriminación en Psicología/fisiología , Factores de Riesgo , Adolescente , Percepción Olfatoria/fisiología , Olfato/fisiologíaRESUMEN
BACKGROUND: Persistent auditory verbal hallucinations (pAVHs) are a fundamental manifestation of schizophrenia (SCZ), yet the exact connection between pAVHs and brain structure remains contentious. This study aims to explore the potential correlation between pAVHs and alterations in grey matter volume (GMV) within specific brain regions among individuals diagnosed with SCZ. METHODS: 76 SCZ patients with pAVHs (pAVH group), 57 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) were investigated using 3 T magnetic resonance imaging. The P3 hallucination item of the Positive and Negative Syndrome Scale was used to assess the severity of pAVHs. Voxel-based morphometry was used to analyze the GMV profile between the three groups. RESULTS: Compared to the non-AVH and HC groups, the pAVH group exhibited extensive reduction in GMV within the frontotemporal cortex. Conversely, no significant difference in GMV was observed between the non-AVH and HC groups. The severity of pAVHs showed a negative correlation with GMV in several regions, including the right fusiform, right inferior temporal, right medial orbitofrontal, right superior frontal, and right temporal pole (p = 0.0036, Bonferroni correction). Stepwise linear regression analysis revealed that GMV in the right temporal pole (ß = -0.29, p = 0.001) and right fusiform (ß = -0.21, p = 0.01) were significantly associated with the severity of pAVHs. CONCLUSIONS: Widespread reduction in GMV is observed within the frontotemporal cortex, particularly involving the right temporal pole and right fusiform, which potentially contribute to the pathogenesis of pAVHs in individuals with chronic SCZ.
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Sustancia Gris , Alucinaciones , Imagen por Resonancia Magnética , Esquizofrenia , Lóbulo Temporal , Humanos , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/patología , Alucinaciones/diagnóstico por imagen , Alucinaciones/etiología , Alucinaciones/patología , Alucinaciones/fisiopatología , Masculino , Femenino , Adulto , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Enfermedad Crónica , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/patología , Persona de Mediana Edad , Adulto Joven , China , Pueblos del Este de AsiaRESUMEN
BACKGROUND AND HYPOTHESIS: Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. STUDY DESIGN: In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. STUDY RESULTS: Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (Pâ <â .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (Pâ <â .05, false discovery rate correction). CONCLUSIONS: Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.
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A subgroup of patients with schizophrenia is believed to have aberrant excess of glutamate in the frontal cortex; this subgroup is thought to show poor response to first-line antipsychotic treatments that focus on dopamine blockade. If we can identify this subgroup early in the course of illness, we can reduce the repeated use of first-line antipsychotics and potentially stratify first-episode patients to intervene early with second-line treatments such as clozapine. The use of proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate and Glx (glutamate plus glutamine) may provide a means for such a stratification. We must first establish if there is robust evidence linking elevations in anterior cingulate cortex (ACC) glutamate metabolites to poor response, and determine if the use of antipsychotics worsens the glutamatergic excess in eventual nonresponders. In this study, we estimated glutamate levels at baseline in 42 drug-naive patients with schizophrenia. We then treated them all with risperidone at a standard dose range of 2-6 mg/day and followed them up for 3 months to categorize their response status. We expected to see baseline "hyperglutamatergia" in nonresponders, and expected this to worsen over time at the follow-up. In line with our predictions, nonresponders had higher glutamate than responders, but patients as a group did not differ in glutamate and Glx from the healthy control (HC) group before treatment-onset (F1,79 = 3.20, p = 0.046, partial η2 = 0.075). Glutamatergic metabolites did not change significantly over time in both nonresponders and responders over the 3 months of antipsychotic exposure (F1,31 = 1.26, p = 0.270, partial η2 = 0.039). We conclude that the use of antipsychotics without prior knowledge of later response delays symptom relief in a subgroup of first-episode patients, but does not worsen the glutamatergic excess seen at the baseline. Given the current practice of nonstratified use of antipsychotics, longer-time follow-up MRS studies are required to see if improvement in symptoms accompanies a dynamic shift in glutamate profile.
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Antipsicóticos , Trastornos Psicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapéutico , Antipsicóticos/farmacología , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/metabolismo , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Ácido Glutámico/metabolismo , Espectroscopía de Protones por Resonancia Magnética/métodos , Glutamina/metabolismoRESUMEN
BACKGROUND: Depression is the second most important cause of disability worldwide. Reducing this major burden on global health requires a better understanding of the etiology, risk factors, and course of the disorder. With the goal of improving the prevention, recognition, and appropriate management of depressive disorders in China, the China Depression Cohort Study will establish a nationally representative sample of at least 85,000 adults (the China Depression Cohort Study-I) and 15,000 middle school students (the China Depression Cohort Study-II) and follow them over time to identify factors that influence the onset, characteristics, and course of depressive disorders. This protocol describes the China Depression Cohort Study-I. METHODS: A multistage stratified random sampling method will be used to identify a nationally representative community-based cohort of at least 85,000 adults (i.e., ≥ 18 years of age) from 34 communities in 17 of mainland China's 31 provincial-level administrative regions. Baseline data collection includes 1) demographic, social and clinical data, 2) diagnostic information, 3) biological samples (i.e., blood, urine, hair), 4) brain MRI scans, and 5) environmental data (e.g., community-level metrics of climate change, air pollution, and socio-economic characteristics). Baseline findings will identify participants with or without depressive disorders. Annual reassessments will monitor potential risk factors for depression and identify incident cases of depression. Cox Proportional-Hazards Regression, Network analysis, Disease trajectory modelling, and Machine learning prediction models will be used to analyze the collected data. The study's main outcomes are the occurrence of depressive disorders; secondary outcomes include adverse behaviors (e.g., self-harm, suicide), the recurrence of depression and the incidence other mental disorders. DISCUSSION: The China Depression Cohort Study-I will collect a comprehensive, nationally representative set of individual-level and community-level variables over time. The findings will reframe the understanding of depression from a 'biology-psychology-society' perspective. This perspective will improve psychiatrists' understanding of depression and, thus, promote the development of more effective subgroup-specific antidepressant drugs and other interventions based on the new biomarkers and relationships identified in the study. TRAIL REGISTRATION: The protocol has been registered on the Chinese Clinical Trial Registry (No. ChiCTR2200059016).
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Contaminación del Aire , Depresión , Adulto , Humanos , China/epidemiología , Estudios de Cohortes , Depresión/epidemiología , Estudios ProspectivosRESUMEN
Introduction: Schizophrenia is a neurodevelopmental disorder, characterized by impairment in reasoning, affectivity, and social relationships. Previous studies have shown delayed motor development and Brain-Derived Neurotrophic Factor (BDNF) level change in individuals with schizophrenia. We researched the month of walking alone (MWA) and BDNF level between drug-naive first-episode schizophrenia patients (FEP) and healthy control (HC), as well as how they behave in neurocognitive function and severity of symptoms. Predictors of schizophrenia were further explored too. Methods: We researched the MWA and BDNF levels between FEP and HCs in the Second Xiangya Hospital of Central South University from August 2017 to January 2020, as well as how they behave in neurocognitive function and the severity of symptoms. A binary logistic regression analysis was used to examine the risk factors affecting the onset and treatment outcome of schizophrenia. Results: We find that FEP showed a walking delay and lower BDNF levels compared to HCs, which were associated with cognitive impairment and severity of symptoms. According to the difference and correlation analysis results, and combined with the appropriate application conditions for binary logistic regression, Wechsler Intelligence Scale Picture completion, Hopkins Verbal Learning Test-Revised, and Trail Making Test: part A were added to the binary logistic regression analysis to distinguish FEP and HCs. Conclusion: Our study has shown delayed motor development and changes in BDNF levels in schizophrenia, extending insight into the early identification of patients with schizophrenia versus healthy populations.
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Protein glycation can result in the formation of advanced glycation end products (AGEs), which pose a potential health risk due to their association with diabetic complications. Natural products are a source of drugs discovery and the search for potential natural inhibitors of AGEs is of great significance. Glucosinolates (GSLs) mainly from cruciferous plants have potential antioxidant, anti-inflammatory, and anti-glycation activities. In this study, the inhibitory activity of GSLs on bovine serum albumin (BSA) along with its mechanism was investigated by virtual screening and various computational simulation techniques. Virtual screening revealed that 174 GSLs were screened using Maestro based on the glide score and 89% of the compounds were found to have potential anti-glycation ability with the docking scores less than -5 kcal/mol. Molecular docking showed that the top 10 GSLs were bound to the IIA structural domain of BSA. Among them, glucohesperin (1) and 2-hydroxyethyl glucosinolate (2) had the lowest docking scores of -9.428 and -9.333 kcal/mol, respectively, reflecting their good binding affinity. Molecular dynamics simulations of 1 (ΔG = -43.46 kcal/mol) and 2 (ΔG = -43.71 kcal/mol) revealed that the complexes of these two compounds with proteins had good stability. Further binding site analysis suggested that the mechanism of inhibition of protein glycation by these two active ingredients might be through competitive hydrogen bonding to maintain the structural integrity of the protein, thus inhibiting glycation reaction. Moreover, the ADMET values and CYP450 metabolism prediction data were within the recommended values. Therefore, it can be concluded that 1 and 2 may act as potential anti-glycation agents.
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Glucosinolatos , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Agentes Antiglicación , Productos Finales de Glicación AvanzadaRESUMEN
Longitudinal observational studies and Mendelian randomization research have obtained contradictory conclusions regarding the association between C-reactive protein (CRP) level and schizophrenia risk. However, the shared genetic mechanisms underlying CRP and schizophrenia remain poorly understood. Here, we examined the global and local genetic correlations using summary statistics from large-scale genome-wide association studies (GWAS) on CRP level and schizophrenia. Furthermore, we identified their shared genetic variants by applying the conditional false discovery rate approach and performed functional analyses of shared variants to explore the shared genetic mechanisms underlying CRP level and schizophrenia. We found a significant negative genetic correlation at the whole genome level and five significant local genetic correlations between CRP level and schizophrenia. Eight-three shared genetic loci were identified, from which single-nucleotide polymorphism (SNP) presents mixed effects on the increased CRP level and schizophrenia risk. Additionally, we identified 64 and 73 candidate genes that were mapped from SNPs with"concordant effect"(ceSNPs) and"discordant effect"(deSNPs) on the CRP level and schizophrenia risk respectively. Functional analyses revealed that genes mapped from ceSNPs and deSNPs exhibited similar patterns of human brain developmental expression trajectories and biological processes, but differed in expression levels and cell-type-specific enrichment in brain tissues. Our findings demonstrated mixed effects of shared genetic architecture between CRP level and schizophrenia, proving a deeper insight into the shared genetic aetiology underlying the CRP level and schizophrenia.
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Proteína C-Reactiva , Esquizofrenia , Humanos , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Esquizofrenia/genética , Estudio de Asociación del Genoma Completo , Sitios Genéticos , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Olfactory discrimination dysfunction has been observed in patients with schizophrenia (SCZ), but its relationship with cognitive function has not been clarified. The purpose of this study was to examine the differences in olfactory identification function in SCZ patients with and without auditory verbal hallucinations (AVHs) and its relationship with cognitive function. Olfactory identification function was measured in 80 SCZ patients with AVHs, 57 SCZ patients without AVHs, and 87 healthy controls (HC). Clinical symptom scores and neuropsychological measures were also administered to all corresponding subjects. Compared to HC, SCZ patients showed significant deficits in olfactory identification and cognitive function, but there were no differences in olfactory identification dysfunction and cognitive dysfunction between the two subgroups. In the non-AVHs subgroup only, poorer Olfactory Stick Identification Test for Japanese (OSIT-J) scores were significantly and positively correlated with total and delayed recall (Bonferroni correction, p < 0.002). Stepwise regression analysis revealed that factors affecting olfactory identification impairment differed in the two SCZ patient subgroups. In conclusion, this study highlights the commonality of olfactory identification dysfunction in SCZ patients and the importance of olfactory assessment of different subtypes of SCZ patients.
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Trastornos del Olfato , Esquizofrenia , Humanos , Alucinaciones , Cognición , Trastornos del Olfato/etiologíaRESUMEN
Schizophrenia has been associated with abnormal intrinsic brain activity, involving various cognitive impairments. Qualitatively similar abnormalities are seen in individuals at ultra-high risk (UHR) for psychosis. In this study, resting-state fMRI (rs-fMRI) data were collected from 44 drug-naïve first-episode schizophrenia (Dn-FES) patients, 48 UHR individuals, and 40 healthy controls (HCs). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and functional connectivity (FC), were performed to evaluate resting brain function. A support vector machine (SVM) was applied for classification analysis. Compared to HCs, both clinical groups showed increased fALFF in the central executive network (CEN), decreased ReHo in the ventral visual pathway (VVP) and decreased FC in temporal-sensorimotor regions. Excellent performance was achieved by using fALFF value in distinguishing both FES (sensitivity=83.21%, specificity=80.58%, accuracy=81.37%, p=0.009) and UHR (sensitivity=75.88%, specificity=85.72%, accuracy=80.72%, p<0.001) from HC group. Moreover, the study highlighted the importance of frontal and temporal alteration in the pathogenesis of schizophrenia. However, no fMRI features were observed that could well distinguish Dn-FES from UHR group. To conclude, fALFF in the CEN may provide potential power for identifying individuals at the early stage of schizophrenia and the alteration in the frontal and temporal lobe may be important to these individuals.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Encéfalo , Mapeo Encefálico , Lóbulo Temporal , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Schizophrenia (SCZ) is a severe and chronic psychiatric disorder with premature age-related physiological changes. However, numerous previous studies examined the epigenetic age acceleration in SCZ patients and yielded inconclusive results. In this study, we propose to explore the epigenetic age acceleration in drug-naive first-episode SCZ (FSCZ) patients and investigate whether epigenetic age acceleration is associated with antipsychotic treatment, psychotic symptoms, cognition, and subcortical volumes. METHODS: We assessed the epigenetic age in 38 drug-naive FSCZ patients and 38 healthy controls by using three independent clocks, including Horvath, Hannum and Levine algorithms. The epigenetic age measurements in SCZ patients were repeated after receiving 8 weeks risperidone monotherapy. RESULTS: Our findings showed significantly positive correlations between epigenetic ages assessed by three clocks and chronological age in both FSCZ patients and healthy controls. Compared with healthy controls, drug-naive FSCZ patients have a significant epigenetic age deceleration in Horvath clock (p = 0.01), but not in Hannum clock (p = 0.07) and Levine clock (p = 0.43). The epigenetic ages of Hannum clock (p = 0.002) and Levine clock (p = 0.01) were significantly accelerated in SCZ patients after 8-week risperidone treatment. However, no significant associations between epigenetic age acceleration and psychotic symptoms, cognitive function, as well as subcortical volumes were observed in FSCZ patients. CONCLUSION: These results demonstrate that distinct epigenetic clocks are sensitive to different aspects of aging process. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Recién Nacido , Lactante , Epigénesis Genética , Metilación de ADN , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Risperidona/farmacología , Risperidona/uso terapéutico , EnvejecimientoRESUMEN
Accumulation of somatic mutations in human neurons is associated with aging and neurodegeneration. To shed light on the somatic mutational burden in Alzheimer's disease (AD) neurons and get more insight into the role of somatic mutations in AD pathogenesis, we performed single-neuron whole genome sequencing to detect genome-wide somatic mutations (single nucleotide variants (SNVs) and Indels) in 96 single prefrontal cortex neurons from 8 AD patients and 8 elderly controls. We found that the mutational burden is â¼3000 somatic mutations per neuron genome in elderly subjects. AD patients have increased somatic mutation burden in AD-related annotation categories, including AD risk genes and differentially expressed genes in AD neurons. Mutational signature analysis showed somatic SNVs (sSNVs) primarily caused by aging and oxidative DNA damage processes but no significant difference was detected between AD and controls. Additionally, functional somatic mutations identified in AD patients showed significant enrichment in several AD-related pathways, including AD pathway, Notch-signaling pathway and Calcium-signaling pathway. These findings provide genetic insights into how somatic mutations may alter the function of single neurons and exert their potential roles in the pathogenesis of AD.
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Enfermedad de Alzheimer , Humanos , Anciano , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secuenciación Completa del Genoma , Envejecimiento/genética , Neuronas/metabolismo , Mutación INDEL , Mutación/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The aim of this study was to investigate the relationship between persistent auditory verbal hallucinations (pAVHs) and N-acetyl-aspartate (NAA) levels in posterior cingulate cortex (PCC). 117 schizophrenia (SCZ) patients (61 pAVHs and 56 non-AVHs) and 66 healthy controls were included. The P3 item of the Positive and Negative Syndrome Scale and the Auditory Hallucinations subscale of the Psychotic Symptom Rating Scale were used to assess the severity of pAVHs. NAA levels were significantly lower in the AVHs group, and were negatively correlated with pAVHs. Therefore, increasing the NAA levels in PCC may be helpful in treating pAVHs.
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Esquizofrenia , Humanos , Esquizofrenia/complicaciones , Esquizofrenia/diagnóstico , Giro del Cíngulo/diagnóstico por imagen , Ácido Aspártico , Pueblos del Este de Asia , Alucinaciones/etiología , Alucinaciones/diagnóstico , Imagen por Resonancia MagnéticaRESUMEN
Background: Individuals who experience the prodromal phase of schizophrenia (SCZ), a common and complex psychiatric disorder, are referred to as ultra-high-risk (UHR) individuals. Short-chain fatty acid (SCFA) is imperative in the microbiota-gut-brain axis and brain function. Accumulating amount of evidence shows the connections between psychiatric disorders and SCFAs. This study aims to explore the underlying roles SCFAs play in SCZ by investigating the association of alterations in SCFAs concentrations with common cognitive functions in both the SCZ and UHR populations. Methods: The study recruited 59 SCZ patients (including 15 participants converted from the UHR group), 51 UHR participants, and 40 healthy controls (HC) within a complete follow-up of 2 years. Results of cognitive functions, which were assessed by utilizing HVLT-R and TMT, and serum concentrations of SCFAs were obtained for all participants and for UHR individuals at the time of their conversion to SCZ. Results: Fifteen UHR participants converted to SCZ within a 2-year follow-up. Valeric acid concentration levels were lower in both the baseline of UHR individuals whom later converted to SCZ (p = 0.046) and SCZ patients (p = 0.036) than the HC group. Additionally, there were lower concentrations of caproic acid in the baseline of UHR individuals whom later transitioned to SCZ (p = 0.019) and the UHR group (p = 0.016) than the HC group. Furthermore, the caproic acid levels in the UHR group are significantly positively correlated with immediate memory (r = 0.355, p = 0.011) and negatively correlated with TMT-B (r = -0.366, p = 0.009). Significant differences in levels of acetic acid, butyric acid and isovaleric acid were absent among the three groups and in UHR individuals before and after transition to SCZ. Conclusion: Our study suggests that alterations in concentrations of SCFAs may be associated with the pathogenesis and the cognitive impairment of schizophrenia. Further researches are warranted to explore this association. The clinical implications of our findings were discussed.
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BACKGROUND: Second generation antipsychotics such as risperidone are first-line pharmacotherapy treatment choices for schizophrenia. However, our ability to reliably predict and monitor treatment reaction is impeded by the lack of relevant biomarkers. As a biomarker for the susceptibility of schizophrenia and clozapine treatment response, DNA methylation (DNAm) has been studied, but the impact of antipsychotics on DNAm has not been explored in drug-naïve patients. OBJECTIVE: The aim of the present study was to examine changes of DNAm after short-term antipsychotic therapy in first-episode drug-naïve schizophrenia (FES) to identify the beneficial and adverse effect of risperidone on DNAm and their relation to treatment outcome. METHODS: Thirty-eight never treated schizophrenia patients and 38 demographically matched individuals (healthy controls) were assessed at baseline and at 8-week follow-up with symptom ratings, and cognitive and functional imaging procedures, at which time a blood draw for DNAm studies was performed. During the 8-week period, patients received treatment with risperidone monotherapy. An independent data set was used as replication. RESULTS: We identified brain related pathways enriched in 4,888 FES-associated CpG sites relative to controls. Risperidone administration in patients altered DNAm in 5,979 CpG sites relative to baseline. Significant group differences in DNAm at follow-up were seen in FES patients at 6,760 CpG sites versus healthy controls. Through comparison of effect size, we found 87.54% out of the risperidone-associated changes in DNAm showed possible beneficial effect, while only 12.46% showed potential adverse effect. There were 580 DNAm sites in which changes shifted methylation levels to be indistinguishable from controls after risperidone treatment. The DNAm changes of some sites that normalized after treatment were correlated with treatment-related changes in symptom severity, spontaneous neurophysiological activity, and cognition. We replicated our results in an independent data set. CONCLUSION: The normalizing effect of risperidone monotherapy on gene DNAm, and its correlation with clinically relevant phenotypes, indicates that risperidone therapy is associated with DNAm changes that are related to changes in brain physiology, cognition and symptom severity.
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Antipsicóticos , Esquizofrenia , Humanos , Risperidona/efectos adversos , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inducido químicamente , Metilación de ADN , Antipsicóticos/efectos adversos , Cognición , Neuroimagen , FenotipoRESUMEN
Schizophrenia and hippocampal volume exhibit a genetic correlation, but the underlying genetic mechanisms remain unclear. Here, we investigated the shared genetic variants in schizophrenia and hippocampal volume using the largest genome-wide association studies (GWASs) data. We identified three genetic loci associated with both schizophrenia and hippocampal volume. Functional annotation analysis suggested that shared genetic variants play a major role via the regulatory effect on gene expression. Expression pattern analyses showed that candidate genes have a spatiotemporal and cell-specific expression pattern across human brain development. These findings provided deeper insights into the genetic mechanisms underlying hippocampus and schizophrenia risk.
Asunto(s)
Esquizofrenia , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Humanos , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMEN
Positive symptoms are marked features of schizophrenia, and emerging evidence has suggested that abnormalities of the brain network underlying these symptoms may play a crucial role in the pathophysiology of the disease. We constructed two brain functional networks based on the positive and negative correlations between positive symptom scores and brain connectivity in drug-naive patients with first-episode schizophrenia (FES, n = 45) by using a machine-learning approach (connectome-based predictive modeling, CPM). The accuracy of the model was r = 0.47 (p = 0.002). The positively and negatively associated network strengths were then compared among FES subjects, individuals at genetic high risk (GHR, n = 41) for schizophrenia, and healthy controls (HCs, n = 48). The results indicated that the positively associated network contained more cross-subnetwork connections (96.02% of 176 edges), with a focus on the default-mode network (DMN)-salience network (SN) and the DMN-frontoparietal task control (FPT) network. The negatively associated network had fewer cross-subnetwork connections (71.79% of 117 edges) and focused on the sensory/somatomotor hand (SMH)-Cingulo opercular task control (COTC) network, the DMN, and the visual network with significantly decreased connectivity in the COTC-SMH network in FES (FES < GHR, p = 0.01; FES < HC, p = 0.01). Additionally, the connectivity strengths of the right supplementary motor area (SMA) (p < 0.001) and the right precentral gyrus (p < 0.0001) were reduced in FES. To the best of our knowledge, this is the first study to generate two brain networks associated with positive symptoms by utilizing CPM in FES. Abnormal segregation, interactions of brain subnetworks, and impaired SMA might lead to salience attribution abnormalities and, thus, as a result, induce positive symptoms in schizophrenia.